Awake prone position in COVID-19-related acute respiratory failure: a meta-analysis of randomized controlled trials

Background We aimed to investigate the effects of awake prone positioning (APP) in nonintubated adult patients with acute hypoxemic respiratory failure due to COVID-19. Methods The PubMed, Embase, Web of Science and Cochrane Central Register databases were searched up to June 1, 2022. All randomized trials investigating the effects of APP were included in the present meta-analysis. The primary outcome was intubation rate, and the secondary outcomes included the length of intensive care unit (ICU) stay, hospital stay, and mortality. Prescribed subgroup analysis was also conducted. Results A total of 10 randomized trials enrolling 2324 patients were ultimately included in the present study. The results indicated that APP was associated with a significant reduction in the intubation rate (OR 0.77, 95% CI 0.63 to 0.93, P = 0.007). However, no differences could be observed in the length of ICU stay or hospitalization or mortality. Subgroup analysis suggested that patients in the ICU settings (OR 0.74, 95% CI 0.60 to 0.91, P = 0.004), patients whose median APP time was more than 4 h (OR 0.77, 95% CI 0.63 to 0.93, P = 0.008), and patients with an average baseline SpO2 to FiO2 ratio less than 200 (OR 0.75, 95% CI 0.61 to 0.92) were more likely to benefit from APP, indicated a significantly reduced intubation rate. Conclusion Based on the current evidence, nonintubated adult patients with hypoxemic respiratory failure due to COVID-19 infection who underwent APP were shown to have a significantly reduced intubation rate. However, no differences in ICU or hospital length of stay or mortality could be observed between APP and usual care. Registration number CRD42022337846 Supplementary Information The online version contains supplementary material available at 10.1186/s12890-023-02442-3.


Ehrmann 2021 Bias
Authors' judgement Support for judgement

Random sequence generation (selection bias) LOW
Quote "…A statistician not involved in patient recruitment generated the allocation sequence for each individual trial…Allocation concealment at randomization was ensured by an online randomization system or with onsite opaque sealed envelopes…" Comments online randomization system ensured the validation of the randomization.

Allocation concealment (selection bias) LOW
Quote "…Allocation concealment at randomization was ensured by an online randomization system or with on-site opaque sealed envelopes…" Comments on-site opaque sealed envelope guaranteed the randomization was concealed from the participants and investigators.

Blinding of participants and personnel (performance bias) HIGH
Quote "…By the very nature of the intervention and design, trial participants, care providers, outcome assessors, and data analysts could not be blinded to the intervention…" Comments To the nature of the study, it was not possible to be blind to the investigators and participants.

Blinding of outcome assessment (detection bias) HIGH
Quote "…By the very nature of the intervention and design, trial participants, care providers, outcome assessors, and data analysts could not be blinded to the intervention…" Comments The study was not blinded to the data analysts.

Incomplete outcome data (attrition bias) LOW
Comments As for all the patients enrolled in this study, all the patients' outcomes were reported with no missing data.

Selective reporting (reporting bias) LOW
Comments All the primary and secondary outcomes described in the method section was reported in the result section with no selective reporting.

Fralick 2022
Bias Authors' judgement Support for judgement

Random sequence generation (selection bias) LOW
Quote "…Central randomization will be stratified by hospital site and performed using an interactive webresponse system…" Comments Central randomization ensured the validity of the randomization, which was not likely to bring bias to the studies.

Allocation concealment (selection bias) UNCERTAIN
Comments The authors gave no info on how the allocation was concealed

Blinding of participants and personnel (performance bias) HIGH
Quote "…The study will be unblinded. It will be impossible to blind patients or physicians. Given the objective nature of the primary outcome and the need for pragmatic approaches in the current clinical situation, an independent, blind clinical events committee is not planed…"

Blinding of outcome assessment (detection bias) UNCERTAIN
Comments The authors did not mention whether the assessors were blinded to the results.

Incomplete outcome data (attrition bias) LOW
Comments As for all the patients enrolled in this study, all the patients' outcomes were reported with no missing data.

Selective reporting (reporting bias) LOW
Comments All the primary and secondary outcomes described in the method section was reported in the result section with no selective reporting.

Other bias LOW
Comments There was no obvious bias pertaining the study

Bias
Authors' judgement Support for judgement

Random sequence generation (selection bias) UNCERTAIN
Quote "…all patients…after randomization the patients divided into two groups…"

Comments
The authors stated the patients were randomised. However, the authors did not describe in detail how the randomization method which would bring bias to the study.

Allocation concealment (selection bias) UNCERTAIN
Comments As nor did the author give any information of how the allocation was concealed, we though this would also bring bias to the study.

Blinding of participants and personnel (performance bias) HIGH
Comments As for the design of the study, it was impossible to blind to the performers.

Blinding of outcome assessment (detection bias) UNCERTAIN
Comments The authors did not give information whether the assessment of outcome was blinded to the statisticians.

Incomplete outcome data (attrition bias) LOW
Comments As for all the patients enrolled in this study, all the patients' outcomes were reported with no missing data.

Selective reporting (reporting bias) LOW
Comments All the primary and secondary outcomes described in the method section was reported in the result section with no selective reporting.

Other bias HIGH
Comments At the baseline information of the patients, PaO2/FiO2 between treatment group and control group was not balanced [126 (88-164) vs. 111 (97 -175), P = 0.036], which we thought would bring potential bias to the results.

Jayakumar 2021
Bias Authors' judgement Support for judgement

Random sequence generation (selection bias) LOW
Quote "…Patients were randomized in blocks of 4 using a computerized random number generator…" Comments Random sequence was generated by computer, which was not likely to bring bias to the result.

Allocation concealment (selection bias) LOW
Quote "…Allocation was concealed using sealed opaque envelopes..." Comments Allocation was concealed from the investigators and participants.
Blinding of participants and personnel (performance bias) HIGH Comments As for the design of the studies, it was not possible to be blinded to the investigators.

Blinding of outcome assessment (detection bias) UNCERTAIN
Comments The authors gave no information whether the outcome assessment was blinded to the investigators or the statisticians.

Incomplete outcome data (attrition bias) LOW
Comments Of all the included patients' data was reported with no missing data.

Selective reporting
(reporting bias) LOW Comments The outcomes described in the method section was reported in the result section, with no missing data.

Other bias UNCERTAIN
Quote "…Our study also has important limitations…onset of illness was not a criterion for inclusion. Some of these patients might have had illness for longer periods than others…" Comments There would be potential unbalance in the severity of illness according to the study design, which would potentially bring bias to the study.

Random sequence generation (selection bias) UNCERTAIN
Quote "… We conducted a nonblinded pragmatic randomized controlled trial in symptomatic patients hospitalized with suspected or laboratory-confirmed COVID-19…" Comments The authors did not describe the details of the randomization, which would bring potential bias to the study.

Allocation concealment (selection bias) UNCERTAIN
Quote "… We conducted a nonblinded pragmatic randomized controlled trial in symptomatic patients hospitalized with suspected or laboratory-confirmed COVID-19…" Comments The authors did not describe the method in detail of the allocation concealment, which would potentially bring bias to the study

Blinding of participants and personnel (performance bias) HIGH
Comments the study did not describe the protocol of how the blinding to the investigators was made. However, according to the nature of this study, it was not possible to be blinded to the investigators.

Blinding of outcome assessment (detection bias) UNCERTAIN
Comments The authors made no description on the blinding of outcome assessment, which would potentially bring bias to the study.

Incomplete outcome data (attrition bias) LOW Comments all the patients' data was reported
Selective reporting (reporting bias) LOW Comments all the outcomes described in the protocol was reported in the result section

Other bias HIGH
Quote "…Interim analysis revealed that protocol adherence was poor…" Comments According to the results section, the median prone time was short of 1.6 (0.2 to 3.1) hours, which was potentially bring bias to the study.

Kharat 2021
Bias Authors' judgement Support for judgement

Random sequence generation (selection bias) UNCERTAIN
Quote "…Six clusters were selected and a computer-generated randomization scheme was used to assign each medical ward randomly in a 1:1 ratio to either the intervention or usual care…"

Allocation concealment (selection bias) UNCERTAIN
Comments the authors gave no information on how the allocation concealment was made, this would potentially bring bias to the study.

Blinding of participants and personnel (performance bias) HIGH
Comments According to the nature of the study, it was not possible for the investigators to be blinded to the allocations.

Blinding of outcome assessment (detection bias) UNCERTAIN
Comments The authors did not mention whether the assessment was blinded to the results, which would potentially bring bias to the study.

Incomplete outcome data (attrition bias) LOW
Comments All the patients' data was reported.

Selective reporting (reporting bias) LOW
Comments All the outcomes were reported

Other bias UNCERTAIN
Comments the follow-up time was 24-hour, prolonged follow-up time may be required for further evaluation of the outcomes.

Rampon 2022
Bias Authors' judgement Support for judgement

Random sequence generation (selection bias) LOW
Quote "…Participants were allocated to the prone positioning intervention arm or the usual care arm using response adaptive randomization based on the posterior probability of the intervention being superior to usual care…." Comments the randomization was not likely to bias to the study.

Allocation concealment (selection bias) HIGH
Quote "…No concealment or blinding will be used in this study. Participants, study personnel, and clinicians will be aware of treatment assignments…." Blinding of participants and personnel (performance bias) HIGH Quote "…No concealment or blinding will be used in this study. Participants, study personnel, and clinicians will be aware of treatment assignments…."

Blinding of outcome assessment (detection bias) UNCERTAIN
Not mentioned

Incomplete outcome data (attrition bias) LOW
Comments All the patients' data was reported.

Selective reporting (reporting bias) LOW
Comments All the outcomes were reported

Other bias HIGH
Quote "…The study began enrollment on April 25, 2020, and halted enrollment on March 25, 2021, after the study met stopping criteria for low enrollment (one or fewer participants enrolled per week for three consecutive weeks)…" Comments As the study stopped earlier than expected, which was much likely to bring bias to the results.

Rosen 2021
Bias Authors' judgement Support for judgement

Random sequence generation (selection bias) LOW
Quote "…Randomization allocation was obtained via a centralized web-based system…" Comments centralized web-base system was validated for random sequence generation, and was not likely to bring bias to the study.

Allocation concealment (selection bias) UNCERTAIN
Comments The authors gave no information on how the allocation concealment was made, and this would potentially bring bias to the results.

Blinding of participants and personnel (performance bias) HIGH
Quote "…Due to the nature of the intervention, the pats, the treating physician, care provider, data collectors and outcome assessors were aware of the allocation…" Comments As stated by the authors, for the design of study, it was not possible to be blinded to the investigators.

Blinding of outcome assessment (detection bias) HIGH
As above

Incomplete outcome data (attrition bias) LOW
Comments All the patients completed the follow-up with no incomplete outcome data.
Selective reporting (reporting bias) LOW Comments All the outcomes described in the method section was reported in the result section.

Other bias UNCERTAIN
Quote "…There are also limitations to this trial. First, the trial was halted early resulting in limited statistical power to detect differences between groups…Forth as all study sites became overwhelmed by severely ill patients with COVID-19, and research staff was relocated for clinical service, we were not able to identify all patients eligible for inclusion…" Comments The performance of the study could potentially bring bias the study.

Tylor 2021
Bias Authors' judgement Support for judgement

Random sequence generation (selection bias) LOW
Quote "…Five medical admitting teams were randomized using computer-generated random numbers. Teams were randomized in a near 1:1 ratio to deliver UC alone (n = 2 clusters) versus UC plus APPS intervention (n = 3 clusters)…" Comments Random sequence was generated by computer, which was not likely to bring bias to the results.

Allocation concealment (selection bias) UNCERTAIN
Comments the authors did not state how the allocation was concealed and this would potentially bring bias to the study.

Blinding of participants and personnel (performance bias) HIGH
Quote "…Clinicians were unblinded to treatment allocation, and enrolled patients were considered unblinded…" Comments According to the protocols, the patients were not blinded to the allocations

Blinding of outcome assessment (detection bias) UNCERTAIN
Quote "…Clinical and safety outcomes were collected from the electronic health recorded study investigators blinded to treatment assignment…" Comments The randomization was blinded to the investigators. However, whether the analysis process was blinded was not described.

Incomplete outcome data (attrition bias) LOW
Comments All the outcomes were reported.
Selective reporting (reporting bias) LOW Comments All the patients' outcomes described in the protocol was reported.

Other bias HIGH
Comments As this was a pilot and feasibility study, and patients enrolled in the study was not adhere to the protocols, and this would potentially bring great bias to the results.